Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

• the invention relates to substituted adenosine-3 ', 5'-phosphoric acid benzyl triesters, a process for their preparation and medicaments containing these compounds.
• Adenosine-3 ', 5'-phosphoric acid benzyl ester (cAMP-benzyl ester, Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 103-111 [1979]) and 8-substituted cAMP derivatives (J.Med.Chem. 1980, 23 242 -251).
• cAMP-benzyl ester Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 103-111 [1979]
• 8-substituted cAMP derivatives J.Med.Chem. 1980, 23 242 -251
• Their positive inotropic effects on isolated guinea pig myocardium are also known. However, these compounds have been shown to show their effects only at relatively high concentrations, i.e. in the millimolar range, which is often already of no interest for systemic use. In some cases there were also negative side effects, for example with dibutyryl-cAMP initially negative inotropic effects were found.
• the object of the invention is therefore to find new substances which show the desired effect in a lower concentration and are as free from side effects as possible.
• the compounds of the invention are prepared by the corresponding adenosine-3 ', 5'-monophosphoric acids substituted in the 8-position according to the method described in J.Med.Chem. 1977, 20, 907-911 specified processes are esterified with the corresponding diazomethanes.
• adenosine-3 ', 5'-monophosphoric acids substituted in the 8-position are converted by halogenation, preferably bromination, from adenosine-3', 5'-monophosphoric acid to 8-halo, preferably 8-bromo-adenosine-3 ', 5' -monophosphoric acid produced and optionally converted into the compounds according to the invention by nucleophilic substitution of the halogen atom analogously to the process given in Biochemistry 10, 2390 (1971).
• Another object of the invention is a process for the preparation of the compounds according to the invention, which is characterized in that a compound of the general formula 8-R 1 -cAMP, 8-R 1 ' -AMP or 8 - R 1 " -AMP, in which R 1 , R 1 ' or R 1 "have the meanings given above and cAMP means adenosine-3', 5'-monophosphoric acid, with a diazomethane derivative of the general formula R 2 CHN 2 , R 2 ' CHN 2 or R 2" CHN 2 , wherein R 2 , R21 or R 2 "have the meanings given above, is esterified.
• the compounds according to the invention are obtained as mixtures, the two components of which differ in that the ester group in the dioxaphosphorinane ring is aligned once axially and once equatorially.
• the general formulas I, I 'and I show the bond between the phosphorus atom and the oxygen atom of the benzyloxy group as a wavy line.
• the separation of the diastereomers is readily possible by chromatography. Since the diastereomers are pharmacologically active If there is no noticeable difference, a separation for use as a medicine is not necessary.
• the invention relates to medicaments which are distinguished by a content of one or more of the compounds according to the invention and the use of the compounds according to the invention in the treatment of diseases of the heart and / or the respiratory tract.
• drugs which also contain a phosphodiesterase inhibiting substance show a potentiated effect which is about 30 to 40 times that of the medicinal products without this additional substance.
• 1-Methyl-3-isobutylxanthine, theophylline and / or papaverine is preferably used as such substance.
• the medicaments are produced by processes known per se, the new compounds or their combinations with phosphodiesterase inhibitors being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of these mixtures is 0.5 to 95, preferably 15 to 75 percent by weight of the total mixture.
• the active substances are used in any suitable formulation, provided that the formation or maintenance of sufficient active substance levels is ensured. This can be achieved, for example, by oral, rectal or parenteral administration in suitable doses.
• the pharmaceutical preparation of the active ingredient is usually in the form of unit doses which are tailored to the desired administration.
• a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
• unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or multiples of a single therapeutic dose.
• a single dose contains preference as the amount of active ingredient that is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, for example in the form of a tablet with a notch.
• compositions according to the invention when in unit doses and for application e.g. are intended for humans, contain about 10 to 500 mg, advantageously 50 to 300 mg and in particular 100 to 300 mg of active ingredient.
• Parenteral preparations can contain about 2 to 40 mg, advantageously 4 to 30 mg and in particular 10 to 25 mg of active ingredient.
• a single dose contains the active ingredient (s) in amounts of 0.05 to 3, preferably 0.1 to 3, in particular 0.5 to 2 mg / kg body weight.
• the active ingredient (s) in a daily dose of 0.5 to 10 mg, preferably 1 to 8 mg, in particular 2 to 5 mg, optionally in the form of several, preferably 1 to 3, single doses administer.
• Preparations for intravenous administration are particularly useful for emergency treatment.
• the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, for example before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal product and the period or Interval within which the administration takes place. So it can be in it may be sufficient in some cases to make do with less than the amount of active ingredient mentioned above, while in other cases the amount of active ingredient mentioned above must be exceeded. In acute cases, a higher dose is given at the start of treatment. After the desired effect occurs, the dose is reduced.
• the pharmaceutical preparations generally consist of the active compounds according to the invention, if desired in combination with phosphodiesterase inhibitors, and non-toxic, pharmaceutically acceptable medicament carriers which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet coating, one Bag or other container for which therapeutically active ingredient are used.
• a carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.
• Tablets, dragees, hard and soft capsules e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
• Tablets can contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. Corn starch or alginates; Binders, e.g. Starch, gelatin or acacia; and lubricants, e.g. Aluminum or magnesium stearate, talc or silicone oil. They can additionally be provided with an upper cover which can also be designed in such a way that it causes a delayed dissolution and absorption of the drug in the gastrointestinal tract, so that e.g. better tolerance, protracting or retardation is achieved.
• Gelatin capsules can mix the drug with a solid, e.g. Calcium carbonate or kaolin, or an oily, e.g. Olive, peanut or paraffin oil, thinners included.
• Aqueous suspensions may include suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone tragacanth or acacia; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
• suspending agents e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone tragacanth or acacia
• oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
• the drugs can be mixed with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavorings and colorants.
• Emulsions can e.g. Olive, peanut or paraffin oil in addition to emulsifiers, e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
• emulsifiers e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
• Suppositories are used for rectal application of the medicinal products, which are produced with the help of binders melting at rectal temperature, for example cocoa butter or polyethylene glycol.
• sterile injectable if necessary short-term, aqueous suspensions, isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.
• the inhalative application of the compounds according to the invention is also preferred. These are administered either directly as a powder or by atomizing solutions or suspensions containing the compounds according to the invention.
• the nebulization can be carried out in a conventional manner, for example by compressed air nebulizers or ultrasound nebulizers. Administration from spray cans, in particular those with a conventional metering valve (metering aerosols), is particularly advantageous. Dosing aerosols make it possible to provide a defined amount of active ingredient per spray. So-called synchronous inhalers are particularly advantageous here, with which the active substance can be delivered synchronously with inhalation. Suitable synchronous inhalation devices are e.g. disclosed in DE-PS 19 45 257, DE-PS 19 17 911 and DE-OS 20 55 734.
• the active ingredients are preferably used in micronized form, particle sizes of less than 10 ⁇ m being advantageous.
• the active compounds are dispersed in customary blowing agents, preferably with the aid of a dispersant.
• Mixtures of trichlorofluoromethane (Frigen®11) and dichlorodifluoromethane (Frigen 1D 12) are particularly suitable as blowing agents, and trichlorofluoromethane can be replaced in whole or in part by 1,1,2-trichlorotrifluoromethane (Frigen®113).
• the sorbitan esters customary for these purposes come as dispersants. (Spane® from Atlas GmbH) and lecithin in question.
• the dispersant is dissolved in the less volatile propellant component which is placed in a cool state.
• the micronized active ingredient or the micronized active ingredients are stirred into the solution.
• the dispersion is filled into spray cans. After crimping, the more volatile blowing agent component is pressed on.
• the active ingredient (s) can, if appropriate, also be formulated in microencapsulated form with one or more of the stated excipients or additives.
• the compounds according to the invention showed a positive inotropic effect on the isolated guinea pig myocardium if there was no positive chronotropic or even negative chronotropic effect; both are desirable for a substance that selectively increases the cardiac strength.
• the mixture of diastereomers was separated by thin layer chromatography, which, however, is not necessary for the pharmacological activity (since additive).
• Papillary muscles from the right ventricle of the guinea pig heart were used to determine positive inotropic effects.
• the adrenergic nerve endings were free of noradrenaline (catecholamine storage by intraperitoneal injection of 5 mg / kg reserpine 24 hours before preparation of the animals).
• the muscles were suspended on an inductive force transducer in a physiological nutrient solution saturated with oxygen (volume 50 ml). The force registration was carried out isometrically, contraction curves were recorded using an ink pen and then analyzed. Before adding the test substance, the muscles were equilibrated with constant irritation (frequency 0.2 Hz, stimulus duration 1 ms) until the force in the nutrient solution had reached a steady state. The concentration of the test substance was increased if the force did not increase within 10 minutes.
• the following table II shows the concentrations of the individual test substances at which the positive inotropic effect was just discernible (threshold concentration) or reached 50% of the maximum force increase (EC 50 ). These values were compared in the lower part of the table with those of known test substances. Furthermore, threshold concentrations and EC 50 values for the test substances listed are given in the presence of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (IBMX) (2 ⁇ 10 -5 mol / l). The result is a shift to 30-40 times lower concentrations compared to the values without phophodiesterase inhibitor. A similar synergism was also observed with papaverine (1 x 10 -5 mol / l) and with theophylline (3 x 10- 4 mol / 1).
• IBMX 1-methyl-3-isobutylxanthine
• Isolated tracheal strips of guinea pigs were used to determine the slackening effect of 8 - CH3S- cAM P -OCH 2 C 6 H 5 (compound 2) on the smooth muscles of the respiratory tract.
• the preparations were suspended as already described. After specifying a suitable test voltage (0.8 g), the sagging effect of the test substance was tested depending on the concentration. After washing out the test substance, the experiment was repeated with an already known cAMP derivative (dibutyryl-cAMP, comparative compound 1).
• Table IV shows the ED 50 (dose of the half-maximum possible relaxation) and the relative potency compared to theophylline for compounds according to the invention.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
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• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1980
  • 1980-07-18 DE DE19803027279 patent/DE3027279A1/de not_active Withdrawn
• 1981
  • 1981-07-15 EP EP81105575A patent/EP0044527A1/fr not_active Withdrawn
  • 1981-07-15 EP EP19810902302 patent/EP0056057A1/fr not_active Withdrawn
  • 1981-07-15 WO PCT/EP1981/000098 patent/WO1982000293A1/fr unknown

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